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RU2413727C2 - Pyrazole derivatives and use thereof as receptor tyrosine kinase inhibitors - Google Patents

Pyrazole derivatives and use thereof as receptor tyrosine kinase inhibitors Download PDF

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RU2413727C2
RU2413727C2 RU2006121337/04A RU2006121337A RU2413727C2 RU 2413727 C2 RU2413727 C2 RU 2413727C2 RU 2006121337/04 A RU2006121337/04 A RU 2006121337/04A RU 2006121337 A RU2006121337 A RU 2006121337A RU 2413727 C2 RU2413727 C2 RU 2413727C2
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formula
pharmaceutically acceptable
compound
acceptable salt
alkyl
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RU2006121337/04A
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RU2006121337A (en
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Майкл Хауард БЛОК (US)
Майкл Хауард БЛОК
Йонсинь ХАНЬ (US)
Йонсинь ХАНЬ
Джон Антони ДЖОУСИ (US)
Джон Антони ДЖОУСИ
Джон У. ЛИ (US)
Джон У. Ли
Дейвид СКОТТ (US)
Дейвид СКОТТ
Бинь ВАН (US)
Бинь Ван
Сася ВАН (US)
Сася ВАН
Тао ВАН (US)
Тао ВАН
Динвэй Ю (US)
Динвэй Ю
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Астразенека Аб
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Abstract

FIELD: chemistry. ^ SUBSTANCE: present invention relates to novel pyrazole derivatives of formula (I) or pharmaceutically acceptable salts thereof, having tyrosine kinase Trk inhibiting properties and used for treating or preventing malignant growths accompanied by high level of Trk, to a method of producing said derivatives, use thereof to prepare a medicinal agent, pharmaceutical compositions based on said derivatives, a method of inhibiting Trk activity and a method of obtaining antiproliferative action. where A denotes a single bond or C1-2alkylene; where the said C1-2alkylene can be optionally substituted with one R22; ring C is a phenyl or a 5-6-member heterocyclic ring with 1-2 heteroatoms selected from N or S. Values of R1-R7, R22 and n are given in the formula of invention. ^ EFFECT: obtaining pharmaceutically acceptable salts having tyrosine kinase Trk inhibiting properties and used for treating or preventing malignant growths. ^ 20 cl, 5 dwg, 193 ex

Description

Текст описания приведен в факсимильном виде.

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The text of the description is given in facsimile form.
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Claims (20)

1. Соединение формулы (I):
Figure 00000143

в которой А представляет собой простую связь или С1-2алкилен; где указанный С1-2алкилен необязательно может быть замещен одним R22;
кольцо С представляет собой фенил или 5-6-членный гетероциклил с 1-2 гетероатомами, выбранными из N или S;
R1 и R4 независимо выбирают из водорода, C1-6алкила, С1-6алкокси, C1-6алкилS(O)а, где а равно 0, С3-6циклоалкила; где R1 и R4 независимо друг от друга необязательно могут быть замещены у атома углерода одним или несколькими R8;
R2 выбирают из гидрокси, амино, С1-6алкила, С1-6алкокси, N-(C1-6алкил)амино, N,N-(С1-6алкил)2амино, N-(С1-6алкил)карбамоила, N,N-(C1-6алкил)2карбамоила или 5-6-членного гетероциклила с 1-2 гетероатомами, выбранными из N, О или S; где R2 необязательно может быть замещен у атома углерода одним-тремя R10;
R3 выбирают из галогена, нитро, циано, C1-6алкила, C1-6алкокси;
R5 представляет собой водород или C1-6алкил;
R6 и R7 независимо выбирают из водорода, галогена, нитро, амино, C1-6алкила, N-(С1-6алкил)амино, C1-6алкоксикарбонила; где R6 и R7 независимо друг от друга необязательно могут быть замещены у атома углерода одним-тремя R15;
или R6 и R7 вместе с пиримидиновой связью, к которой они присоединены, образуют 5- или 6-членное карбоциклическое кольцо или 5- или 6-членное гетероциклическое кольцо с 1-2 гетероатомами, выбранными из N или S, где указанное карбоциклическое кольцо или гетероциклическое кольцо необязательно может быть замещено у атома углерода одним R17;
n=0 или 1;
R10, R15, R17 и R22 независимо выбирают из галогена, гидрокси, амино, карбокси, С1-6алкила, C1-6алкокси; где R17 может быть необязательно замещен у атома углерода одним R19;
R19 выбирают из С1-6алкокси или 5-6-членного гетероциклила с 1-2 гетероатомами, выбранными из N или О; где R19 необязательно может быть замещен у атома углерода одним R23;
R23 представляет собой метил;
или его фармацевтически приемлемая соль;
при условии, что указанное соединение не представляет собой:
5-бром-N4-(5-метил-1H-пиразол-3-ил)-N2-[1-(2-пиридинил)пропил]-2,4-пиримидиндиамин;
5-хлор-N4-(5-метил-1H-пиразол-3-ил)-N2-[1-(2-пиридинил)пропил]-2,4-пиримидиндиамин;
5-бром-N2-[1-(3-метил-5-изоксазолил)этил]-N4-(5-метил-1Н-пиразол-3-ил)-2,4-пиримидиндиамин;
5-хлор-N2-[1-(3-метил-5-изоксазолил)этил]-N4-(5-метил-1H-пиразол-3-ил)-2,4-пиримидиндиамин;
5-бром-N4-(5-метил-1H-пиразол-3-ил)-N2-[1-(3-пиридинил)пропил]-2,4-пиримидиндиамин;
5-хлор-N4-(5-метил-1H-пиразол-3-ил)-N2-[1-(3-пиридинил)пропил]-2,4-пиримидиндиамин;
5-хлор-N4-(5-метил-1H-пиразол-3-ил)-N2-[1-(3-пиридинил)этил]-2,4-пиримидиндиамин;
5-бром-N4-(5-метил-1H-пиразол-3-ил)-N2-[1-(3-пиридинил)этил]-2,4-пиримидиндиамин; или
5-бром-N4-(5-метил-1H-пиразол-3-ил)-N2-[1-(2-пиридинил)этил]-2,4-пиримидиндиамин.1. The compound of formula (I):
Figure 00000143

in which A represents a single bond or C 1-2 alkylene; wherein said C 1-2 alkylene may optionally be substituted with one R 22 ;
ring C represents phenyl or a 5-6 membered heterocyclyl with 1-2 heteroatoms selected from N or S;
R 1 and R 4 are independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl S (O) a , where a is 0, C 3-6 cycloalkyl; where R 1 and R 4 independently of one another may optionally be substituted at the carbon atom by one or more R 8 ;
R 2 is selected from hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, N- (C 1-6 alkyl) amino, N, N- (C 1-6 alkyl) 2 amino, N- (C 1 -6 alkyl) carbamoyl, N, N- (C 1-6 alkyl) 2 carbamoyl or 5-6 membered heterocyclyl with 1-2 heteroatoms selected from N, O or S; where R 2 optionally may be substituted at the carbon atom by one to three R 10 ;
R 3 is selected from halogen, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy;
R 5 represents hydrogen or C 1-6 alkyl;
R 6 and R 7 are independently selected from hydrogen, halogen, nitro, amino, C 1-6 alkyl, N- (C 1-6 alkyl) amino, C 1-6 alkoxycarbonyl; where R 6 and R 7 independently of one another may optionally be substituted at the carbon atom with one to three R 15 ;
or R 6 and R 7 together with the pyrimidine bond to which they are attached form a 5- or 6-membered carbocyclic ring or a 5- or 6-membered heterocyclic ring with 1-2 heteroatoms selected from N or S, wherein said carbocyclic ring or the heterocyclic ring may optionally be substituted on the carbon atom with one R 17 ;
n is 0 or 1;
R 10 , R 15 , R 17 and R 22 are independently selected from halogen, hydroxy, amino, carboxy, C 1-6 alkyl, C 1-6 alkoxy; where R 17 may optionally be substituted at the carbon atom with one R 19 ;
R 19 is selected from C 1-6 alkoxy or a 5-6 membered heterocyclyl with 1-2 heteroatoms selected from N or O; where R 19 optionally can be substituted at the carbon atom with one R 23 ;
R 23 represents methyl;
or a pharmaceutically acceptable salt thereof;
provided that the specified connection does not represent:
5-bromo-N 4 - (5-methyl-1H-pyrazol-3-yl) -N 2 - [1- (2-pyridinyl) propyl] -2,4-pyrimidinediamine;
5-chloro-N 4 - (5-methyl-1H-pyrazol-3-yl) -N 2 - [1- (2-pyridinyl) propyl] -2,4-pyrimidinediamine;
5-bromo-N 2 - [1- (3-methyl-5-isoxazolyl) ethyl] -N 4 - (5-methyl-1H-pyrazol-3-yl) -2,4-pyrimidinediamine;
5-chloro-N 2 - [1- (3-methyl-5-isoxazolyl) ethyl] -N 4 - (5-methyl-1H-pyrazol-3-yl) -2,4-pyrimidinediamine;
5-bromo-N 4 - (5-methyl-1H-pyrazol-3-yl) -N 2 - [1- (3-pyridinyl) propyl] -2,4-pyrimidinediamine;
5-chloro-N 4 - (5-methyl-1H-pyrazol-3-yl) -N 2 - [1- (3-pyridinyl) propyl] -2,4-pyrimidinediamine;
5-chloro-N 4 - (5-methyl-1H-pyrazol-3-yl) -N 2 - [1- (3-pyridinyl) ethyl] -2,4-pyrimidinediamine;
5-bromo-N 4 - (5-methyl-1H-pyrazol-3-yl) -N 2 - [1- (3-pyridinyl) ethyl] -2,4-pyrimidinediamine; or
5-bromo-N 4 - (5-methyl-1H-pyrazol-3-yl) -N 2 - [1- (2-pyridinyl) ethyl] -2,4-pyrimidinediamine. 2. Соединение формулы (I) или его фармацевтически приемлемая соль по п.1, где А представляет собой простую связь.2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein A is a single bond. 3. Соединение формулы (I) или его фармацевтически приемлемая соль по п.1, где R4 представляет собой водород.3. The compound of formula (I) or its pharmaceutically acceptable salt according to claim 1, where R 4 represents hydrogen. 4. Соединение формулы (I) или его фармацевтически приемлемая соль по п.1, где R2 выбирают из C1-6алкила.4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 is selected from C 1-6 alkyl. 5. Соединение формулы (I) или его фармацевтически приемлемая соль по п.1, где R3 представляет собой фтор.5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 3 is fluoro. 6. Соединение формулы (I) или его фармацевтически приемлемая соль по п.1, где R5 представляет собой водород.6. The compound of formula (I) or its pharmaceutically acceptable salt according to claim 1, where R 5 represents hydrogen. 7. Способ получения соединения формулы (I) или его фармацевтически приемлемой соли по любому из пп.1-6, включающий взаимодействие пиримидина формулы (IV):
Figure 00000144

где L представляет собой вытесняемую группу;
с соединением формулы (V):
Figure 00000145

и затем, при необходимости:
i) превращение соединения формулы (I) в другое соединение формулы (I);
ii) удаление любых защитных групп;
iii) образование фармацевтически приемлемой соли.7. A method of obtaining a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, comprising reacting a pyrimidine of formula (IV):
Figure 00000144

where L is a displaceable group;
with a compound of formula (V):
Figure 00000145

and then, if necessary:
i) converting a compound of formula (I) into another compound of formula (I);
ii) removal of any protecting groups;
iii) the formation of a pharmaceutically acceptable salt. 8. Соединение формулы (I) или его фармацевтически приемлемая соль по п.1 для применения в качестве лекарственного средства, обладающего ингибирующими свойствами в отношении тирозинкиназы Trk.8. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 for use as a medicine having Trk tyrosine kinase inhibitory properties. 9. Применение соединения формулы (I) или его фармацевтически приемлемой соли по любому из пп.1-6 для приготовления лекарственного средства для применения для ингибирования активности Trk.9. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 for the preparation of a medicament for use to inhibit Trk activity. 10. Применение соединения формулы (I) или его фармацевтически приемлемой соли по любому из пп.1-6 для приготовления лекарственного средства для применения для лечения или профилактики злокачественного новообразования, сопровождающегося повышением уровня Trk.10. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 for the preparation of a medicament for use in the treatment or prevention of malignant neoplasm accompanied by an increase in Trk level. 11. Применение соединения формулы (I) или его фармацевтически приемлемой соли по любому из пп.1-6 для приготовления лекарственного средства, обладающего антипролиферативным действием.11. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 for the preparation of a medicament having antiproliferative effect. 12. Способ ингибирования активности Trk, включающий введение терапевтически эффективного количества соединения формулы (I) или его фармацевтически приемлемой соли по любому из пп.1-6.12. A method of inhibiting Trk activity, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6. 13. Способ получения антипролиферативного действия, который предусматривает введение эффективного количества соединения формулы (I) или его фармацевтически приемлемой соли по любому из пп.1-6.13. A method for producing an antiproliferative effect, which comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6. 14. Фармацевтическая композиция, содержащая эффективное количество соединения формулы (I) или его фармацевтически приемлемой соли по любому из пп.1-6 вместе с по меньшей мере одним фармацевтически приемлемым носителем, разбавителем или наполнителем, для применения для ингибирования активности Trk.14. A pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, together with at least one pharmaceutically acceptable carrier, diluent or excipient, for use to inhibit Trk activity. 15. Фармацевтическая композиция, содержащая эффективное количество соединения формулы (I) или его фармацевтически приемлемой соли по любому из пп.1-6 вместе с по меньшей мере одним фармацевтически приемлемым носителем, разбавителем или наполнителем, для применения для лечения или профилактики злокачественного новообразования, сопровождающегося повышением уровня Trk.15. A pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, together with at least one pharmaceutically acceptable carrier, diluent or excipient, for use in the treatment or prevention of a malignant neoplasm accompanied by increase in Trk. 16. Фармацевтическая композиция, содержащая эффективное количество соединения формулы (I) или его фармацевтически приемлемой соли по любому из пп.1-6 вместе с по меньшей мере одним фармацевтически приемлемым носителем, разбавителем или наполнителем, для получения антипролиферативного действия.16. A pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, together with at least one pharmaceutically acceptable carrier, diluent or excipient, to obtain an antiproliferative effect. 17. Соединение формулы (I) или его фармацевтически приемлемая соль по п.1 для применения для ингибирования активности Trk.17. The compound of formula (I) or its pharmaceutically acceptable salt according to claim 1 for use to inhibit Trk activity. 18. Соединение формулы (I) или его фармацевтически приемлемая соль по п.1 для применения для лечения или профилактики злокачественного новообразования, сопровождающегося повышением уровня Trk.18. The compound of formula (I) or its pharmaceutically acceptable salt according to claim 1 for use in the treatment or prevention of malignant neoplasms, accompanied by an increase in the level of Trk. 19. Соединение формулы (I) или его фармацевтически приемлемая соль по любому из пп.1-6 для получения антипролиферативного действия.19. The compound of formula (I) or its pharmaceutically acceptable salt according to any one of claims 1 to 6 to obtain antiproliferative effects. 20. Применение по п.10, где указанное злокачественное новообразование выбирают из рака яичников, рака молочной железы, рака прямой кишки и рака предстательной железы. 20. The use of claim 10, where the specified malignant neoplasm is selected from ovarian cancer, breast cancer, colorectal cancer and prostate cancer.
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